Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver

Avinash Thakur, Jasper C.H. Wong, Evan Y. Wang, Jeremy Lotto, Donghwan Kim, Jung Chien Cheng, Matthew Mingay, Rebecca Cullum, Vaishali Moudgil, Nafeel Ahmed, Shu Huei Tsai, Wei Wei, Colum P. Walsh, Tabea Stephan, Misha Bilenky, Bettina M. Fuglerud, Mohammad M. Karimi, Frank J. Gonzalez, Martin Hirst, Pamela A. Hoodless

    Research output: Contribution to journalArticle

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    Abstract

    Cell-fate determination is influenced by interactions between master transcription factors (TFs) and cis-regulatory elements. Hepatocyte nuclear factor 4 alpha (HNF4A), a liver-enriched TF, acts as a master controller in specification of hepatic progenitor cells by regulating a network of TFs to control onset of hepatocyte cell fate. Using analysis of genome-wide histone modifications, DNA methylation, and hydroxymethylation in mouse hepatocytes, we show that HNF4A occupies active enhancers in hepatocytes and is essential for active histone and DNA signatures, especially acetylation of lysine 27 of histone 3 (H3K27ac) and 5-hydroxymethylcytosine (5hmC). In mice lacking HNF4A protein in hepatocytes, we observed a decrease in both H3K27ac and hydroxymethylation at regions bound by HNF4A. Mechanistically, HNF4A-associated hydroxymethylation (5hmC) requires its interaction with ten-eleven translocation methylcytosine dioxygenase 3 (TET3), a protein responsible for oxidation from 5mC to 5hmC. Furthermore, HNF4A regulates TET3 expression in liver by directly binding to an enhancer region. Conclusion: In conclusion, we identified that HNF4A is required for the active epigenetic state at enhancers that amplifies transcription of genes in hepatocytes.

    LanguageEnglish
    JournalHepatology
    Early online date1 Apr 2019
    DOIs
    Publication statusPublished - 1 Apr 2019

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    Hepatocyte Nuclear Factor 4
    Epigenomics
    Hepatocytes
    Liver
    Dioxygenases
    Transcription Factors
    Histones
    Histone Code
    DNA Methylation
    Acetylation
    Lysine
    Proteins
    Stem Cells
    Genome
    DNA

    Cite this

    Thakur, A., Wong, J. C. H., Wang, E. Y., Lotto, J., Kim, D., Cheng, J. C., ... Hoodless, P. A. (2019). Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver. Hepatology. https://doi.org/10.1002/hep.30631
    Thakur, Avinash ; Wong, Jasper C.H. ; Wang, Evan Y. ; Lotto, Jeremy ; Kim, Donghwan ; Cheng, Jung Chien ; Mingay, Matthew ; Cullum, Rebecca ; Moudgil, Vaishali ; Ahmed, Nafeel ; Tsai, Shu Huei ; Wei, Wei ; Walsh, Colum P. ; Stephan, Tabea ; Bilenky, Misha ; Fuglerud, Bettina M. ; Karimi, Mohammad M. ; Gonzalez, Frank J. ; Hirst, Martin ; Hoodless, Pamela A. / Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver. In: Hepatology. 2019.
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    title = "Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver",
    abstract = "Cell-fate determination is influenced by interactions between master transcription factors (TFs) and cis-regulatory elements. Hepatocyte nuclear factor 4 alpha (HNF4A), a liver-enriched TF, acts as a master controller in specification of hepatic progenitor cells by regulating a network of TFs to control onset of hepatocyte cell fate. Using analysis of genome-wide histone modifications, DNA methylation, and hydroxymethylation in mouse hepatocytes, we show that HNF4A occupies active enhancers in hepatocytes and is essential for active histone and DNA signatures, especially acetylation of lysine 27 of histone 3 (H3K27ac) and 5-hydroxymethylcytosine (5hmC). In mice lacking HNF4A protein in hepatocytes, we observed a decrease in both H3K27ac and hydroxymethylation at regions bound by HNF4A. Mechanistically, HNF4A-associated hydroxymethylation (5hmC) requires its interaction with ten-eleven translocation methylcytosine dioxygenase 3 (TET3), a protein responsible for oxidation from 5mC to 5hmC. Furthermore, HNF4A regulates TET3 expression in liver by directly binding to an enhancer region. Conclusion: In conclusion, we identified that HNF4A is required for the active epigenetic state at enhancers that amplifies transcription of genes in hepatocytes.",
    author = "Avinash Thakur and Wong, {Jasper C.H.} and Wang, {Evan Y.} and Jeremy Lotto and Donghwan Kim and Cheng, {Jung Chien} and Matthew Mingay and Rebecca Cullum and Vaishali Moudgil and Nafeel Ahmed and Tsai, {Shu Huei} and Wei Wei and Walsh, {Colum P.} and Tabea Stephan and Misha Bilenky and Fuglerud, {Bettina M.} and Karimi, {Mohammad M.} and Gonzalez, {Frank J.} and Martin Hirst and Hoodless, {Pamela A.}",
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    Thakur, A, Wong, JCH, Wang, EY, Lotto, J, Kim, D, Cheng, JC, Mingay, M, Cullum, R, Moudgil, V, Ahmed, N, Tsai, SH, Wei, W, Walsh, CP, Stephan, T, Bilenky, M, Fuglerud, BM, Karimi, MM, Gonzalez, FJ, Hirst, M & Hoodless, PA 2019, 'Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver', Hepatology. https://doi.org/10.1002/hep.30631

    Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver. / Thakur, Avinash; Wong, Jasper C.H.; Wang, Evan Y.; Lotto, Jeremy; Kim, Donghwan; Cheng, Jung Chien; Mingay, Matthew; Cullum, Rebecca; Moudgil, Vaishali; Ahmed, Nafeel; Tsai, Shu Huei; Wei, Wei; Walsh, Colum P.; Stephan, Tabea; Bilenky, Misha; Fuglerud, Bettina M.; Karimi, Mohammad M.; Gonzalez, Frank J.; Hirst, Martin; Hoodless, Pamela A.

    In: Hepatology, 01.04.2019.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver

    AU - Thakur, Avinash

    AU - Wong, Jasper C.H.

    AU - Wang, Evan Y.

    AU - Lotto, Jeremy

    AU - Kim, Donghwan

    AU - Cheng, Jung Chien

    AU - Mingay, Matthew

    AU - Cullum, Rebecca

    AU - Moudgil, Vaishali

    AU - Ahmed, Nafeel

    AU - Tsai, Shu Huei

    AU - Wei, Wei

    AU - Walsh, Colum P.

    AU - Stephan, Tabea

    AU - Bilenky, Misha

    AU - Fuglerud, Bettina M.

    AU - Karimi, Mohammad M.

    AU - Gonzalez, Frank J.

    AU - Hirst, Martin

    AU - Hoodless, Pamela A.

    PY - 2019/4/1

    Y1 - 2019/4/1

    N2 - Cell-fate determination is influenced by interactions between master transcription factors (TFs) and cis-regulatory elements. Hepatocyte nuclear factor 4 alpha (HNF4A), a liver-enriched TF, acts as a master controller in specification of hepatic progenitor cells by regulating a network of TFs to control onset of hepatocyte cell fate. Using analysis of genome-wide histone modifications, DNA methylation, and hydroxymethylation in mouse hepatocytes, we show that HNF4A occupies active enhancers in hepatocytes and is essential for active histone and DNA signatures, especially acetylation of lysine 27 of histone 3 (H3K27ac) and 5-hydroxymethylcytosine (5hmC). In mice lacking HNF4A protein in hepatocytes, we observed a decrease in both H3K27ac and hydroxymethylation at regions bound by HNF4A. Mechanistically, HNF4A-associated hydroxymethylation (5hmC) requires its interaction with ten-eleven translocation methylcytosine dioxygenase 3 (TET3), a protein responsible for oxidation from 5mC to 5hmC. Furthermore, HNF4A regulates TET3 expression in liver by directly binding to an enhancer region. Conclusion: In conclusion, we identified that HNF4A is required for the active epigenetic state at enhancers that amplifies transcription of genes in hepatocytes.

    AB - Cell-fate determination is influenced by interactions between master transcription factors (TFs) and cis-regulatory elements. Hepatocyte nuclear factor 4 alpha (HNF4A), a liver-enriched TF, acts as a master controller in specification of hepatic progenitor cells by regulating a network of TFs to control onset of hepatocyte cell fate. Using analysis of genome-wide histone modifications, DNA methylation, and hydroxymethylation in mouse hepatocytes, we show that HNF4A occupies active enhancers in hepatocytes and is essential for active histone and DNA signatures, especially acetylation of lysine 27 of histone 3 (H3K27ac) and 5-hydroxymethylcytosine (5hmC). In mice lacking HNF4A protein in hepatocytes, we observed a decrease in both H3K27ac and hydroxymethylation at regions bound by HNF4A. Mechanistically, HNF4A-associated hydroxymethylation (5hmC) requires its interaction with ten-eleven translocation methylcytosine dioxygenase 3 (TET3), a protein responsible for oxidation from 5mC to 5hmC. Furthermore, HNF4A regulates TET3 expression in liver by directly binding to an enhancer region. Conclusion: In conclusion, we identified that HNF4A is required for the active epigenetic state at enhancers that amplifies transcription of genes in hepatocytes.

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    U2 - 10.1002/hep.30631

    DO - 10.1002/hep.30631

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